ArticleMolecular oncology2018
Dabrafenib inhibits the growth of BRAF-WT cancers through CDK16 and NEK9 inhibition.
Article in Molecular oncology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
33 citing papers in PubMed, 1 synthesis or guideline pooled it, 41 citations in OpenAlex.
- COVID-19 outbreak: history, mechanism, transmission, structural studies and therapeutics.Infection · 2021Pooled it
- Cyclins and Cyclin-Dependent Kinases: Structure, Biological Functions, and Innovative Targeting Strategies in Cancer.MedComm · 2026Review
- The Role of Transcriptional and Atypical Cyclin-Dependent Protein Kinases in Melanoma.Cancers · 2026Review
- Structural basis of the cyclin Y/14-3-3 protein-mediated activation of CDK16.Nature communications · 2026Article
- NEK9-mediated Wnt signalling repressor TLE3 rewires Docetaxel resistance in cancer cells by inducing pyroptosis.British journal of cancer · 2025Article
- Hydroxytyrosol Reprograms the Tumor Microenvironment in 3D Melanoma Models by Suppressing ERBB Family and Kinase Pathways.International journal of molecular sciences · 2025Article
- NEK kinases in cell cycle regulation, DNA damage response, and cancer progression.Tissue & cell · 2025Review
- In silico study to identify novel NEK7 inhibitors from natural sources by a combination strategy.Molecular diversity · 2025Article
- Novel Small Molecule Inhibitors of Cyclin-dependent Kinases as Anticancer Agents.Current medicinal chemistry · 2025Review
- The NIMA-related kinase family and cancer.Frontiers in oncology · 2025Review
- Multi-output prediction of dose-response curves enables drug repositioning and biomarker discovery.NPJ precision oncology · 2024Article
- Exploring markers of immunoresponsiveness in papillary thyroid carcinoma and future treatment strategies.Journal for immunotherapy of cancer · 2024Article
- Dabrafenib Alters MDSC Differentiation and Function by Activation of GCN2.Cancer research communications · 2024Article
- Illumination of understudied ciliary kinases.Frontiers in molecular biosciences · 2024Review
- Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2.International journal of molecular sciences · 2023Review
- Cancer associated fibroblast derived SLIT2 drives gastric cancer cell metastasis by activating NEK9.Cell death & disease · 2023Article
- CDK6 is activated by the atypical cyclin I to promote E2F-mediated gene expression and cancer cell proliferation.Molecular oncology · 2023Article
- Dabrafenib-Panobinostat Salt: Improving the Dissolution Rate and Inhibition of BRAF Melanoma Cells.ACS omega · 2023Article
- Proteomic characterization of post-translational modifications in drug discovery.Acta pharmacologica Sinica · 2022Review
- Head-to-Head Comparison of BRAF/MEK Inhibitor Combinations Proposes Superiority of Encorafenib Plus Trametinib in Melanoma.Cancers · 2022Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
Abstract
Although the BRAF inhibitors dabrafenib and vemurafenib have both proven successful against BRAF-mutant melanoma, there seem to be differences in their mechanisms of action. Here, we show that dabrafenib is more effective at inhibiting the growth of NRAS-mutant and KRAS-mutant cancer cell lines than vemurafenib. Using mass spectrometry-based chemical proteomics, we identified NEK9 and CDK16 as unique targets of dabrafenib. Both NEK9 and CDK16 were highly expressed in specimens of advanced melanoma, with high expression of both proteins correlating with a worse overall survival. A role for NEK9 in the growth of NRAS- and KRAS-mutant cell lines was suggested by siRNA studies in which silencing was associated with decreased proliferation, cell cycle arrest associated with increased p21 expression, inhibition of phospho-CHK1, decreased CDK4 expression, and the initiation of a senescence response. Inhibition of CDK4 but not CHK1 recapitulated the effects of NEK9 silencing, indicating this to be the likely mechanism of growth inhibition. We next turned our attention to CDK16 and found that its knockdown inhibited the phosphorylation of the Rb protein at S780 and increased expression of p27. Both of these effects were phenocopied in NRAS- and KRAS-mutant cancer cells by dabrafenib, but not vemurafenib. Combined silencing of NEK9 and CDK16 was associated with enhanced inhibition of melanoma cell proliferation. In summary, we have identified dabrafenib as a potent inhibitor of NEK9 and CDK16, and our studies suggest that inhibition of these kinases may have activity against cancers that do not harbor BRAF mutations.
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